Variants of varying clinical consequence (VVCCs) are associated with differing penetrance and expressivity in...

An unintended consequence of cystic fibrosis (CF) newborn bloodspot screening (NBS) is the identification of infants who have an abnormal NBS but do not meet the clinical diagnostic criteria for CF, known as CFTR-related metabolic syndrome (CRMS) in the US or CF screen positive, inconclusive diagnosis (CFSPID) in other countries. Many children with CRMS/CFSPID harbor at least one CFTR variant of varying clinical consequences (VVCC), a category associated with varying penetrance for CF. We sought to determine whether particular VVCCs are associated with differing risks of diagnostic transition (or conversion) from CRMS/CFSPID to CF.

We performed a meta-analysis of published CRMS/CFSPID cases and examined CF penetrance (i.e. conversion from CRMS/CFSPID to CF) associated with specific VVCCs. We examined expressivity by evaluating the symptoms associated with CF conversion for each individual VVCC and by overall group.

There were 606 children with CRMS/CFSPID in 25 manuscripts. Of 268 children with CRMS/CFSPID harboring one VVCC and one CF-causing variant, 78 (28%) converted to CF. There was wide variability in VVCC penetrance; some variants (5T;TG13, Q1476X, P5L) were associated with a high risk of CF conversion (≥50%) whereas others (F1052V, R117H;7T, D1270N) were associated with a low risk. Expressivity associated with VVCCs varied substantially, with elevated sweat chloride concentration most commonly observed in CF conversions.

There is significant variability in the penetrance and expressivity associated with VVCCs. Results can inform clinicians and families and guide policy regarding inclusion of VVCCs in CF NBS.